Enterotoxigenic Escherichia coli (ETEC) and enteropathogenic E. coli (EPEC) are common causes of diarrhea among children in developing countries. ETEC is also the most common cause of traveler's diarrhea in adults. ETEC strains produce either the heat-Iabile toxin, L T, or heat-stable toxin, ST (also called STa) or both. EPEC does not produce any known toxins, and the way that it triggers diarrhea is still not clear. ETEC and EPEC are commonly isolated together as dual infections in the same patient. The discovery that EPEC triggers host cell death provided an important lead in how EPEC causes disease. The mode of cell death triggered by EPEC has features of both apoptosis (programmed cell death) and necrosis. One of the non-apoptotic features of EPEC-mediated killing is release of adenosine triphosphate (ATP) from the host cell. Once released, ATP is broken down to ADP, AMP, and adenosine. Adenosine itself acts as a potent secretagogue, i.e, a stimulator of intestinal fluid and electrolyte secretion, which may cause or contribute to watery diarrhea. Results from the applicant's laboratory show that cellular signaling events triggered by EPEC specifically increase the activity of ETEC STa toxin via EPEC-mediated changes in protein kinase C (PKC) and tight junctions. Furthermore, the E. coli LT toxin potentiates the ATP release triggered by EPEC infection. Therefore, ETEC and EPEC are able, at least in vitro, to mutually enhance the virulence of the other. The goals of this application are to understand molecular mechanisms by which dual infections with ETEC and EPEC generate "cross-talk" between signaling pathways in the host, and how this cross-talk is coupled to increased secretion of fluid and electrolytes in the intestinal tract.